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INTERNATIONAL JOURNAL OF ADVANCES IN PHARMACY, BIOLOGY AND CHEMISTRY Research Article Formulation and Evaluation of Rabeprazole Sodium Enteric Coated Pellets KL. Senthilkumar*, M. Muthukumaran and B. Chenchuratnam
Padmavathi College of Pharmacy & Research Institute, Dharmapuri, Tamilnadu, India.
ABSTRACTThe aim of the present investigation was to prepare delayed release i.e., enteric coated pel ets of Rabeprazole
sodium by using hydroxyproply methyl cel ulose based sub coating and methacrylic acid copolymer based enteric
coating. The different batches of pel ets were prepared by drug suspension layering method. Comparatrive
study of dissolution profile of final batch with market preparations was conducted and it was concluded that final
batch shown good similarity with market products. The results of the accelerated stability of final formulation
revealed that storage conditions were excel ent.
Keywords: Rabeprazole sodium, sub coating, enteric coating. INTRODUCTION
The first aim of present work was to prepare Delayed
Proton Pump Inhibitors (PPIs) are used in the
release i.e., enteric coated pellets of Rabeprazole
treatment of acid – related gastro – duodenal
sodium by using Methacrylic acid copolymer in
disorders by reducing gastric acid secretion. Proton
Fluid bed processor to prevent degradation in the
pump inhibitors are substituted benzimidazoles and
stomach due to the acidic environment or gastric
all share a similar core structure and mode of action,
enzymes and compare with the market sample
but differ in substituent groups. The type of
substituents affects the chemical properties of the
MATERIALS
compounds that directly influence their rates of
Rabeprazole Sodium (I.H.S) Mannitol (Pearlitol
reactions and therefore their stability in different
SD200), Sodium Carbonate (I.P), Polyplasdone XL,
media. The stability of PPIs in aqueous media is a
XL-10 (ISP), Talc (I.P), Opadry clears (Colorcon),
function of PH with an increased rate of degradation
as the PH decreases. Degradation of the Rabeprazole
leads to a yellow or purple discoloration of the
EXPERIMENTAL
pellets, film layer or dissolution medium. Stability of
Preformulation studies
Rabeprazole sodium also decreases under moisture
Preformulation studies were carried out for
conditions. Exposure of Rabeprazole sodium to the
appropriate selection of excipients in view of
acidic content of the stomach would lead to
Rabeprazole Sodium modified release pellets.
significant degradation of the drug and hence,
Micromeritic properties of Rabeprazole Sodium
Delayed release dosage form is best formulations
1. Angle of repose
which are used for drugs that are destroyed in the
The angle of repose of Rabeprazoe powder were
gastric fluids, or cause gastric irritation or are
determined by the funnel method. The accurately
absorbed preferentially in the intestine. Such
weight powder blend were taken in the funnel. The
preparations contain an alkaline core material
height of the funnel was adjusted in such a way the
comprising the active substance, a separating layer
tip of the funnel just touched the apex of the powder
blend. The powder blend was allowed to flow through the funnel freely on to the surface. The
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diameter of the powder cone was measured and angle Table 1: Compatibility study of Rabeprazole
of repose was calculated using the following
sodium with excipients tan θ = h/r Diluents Excipients /75%RH±5%
Where h and r are the height and radius of the powder
2. Bulk Density and tapped Density
Both Bulk density (BD) and tapped density (TD) was
determined. A quantity of 2 gm of Rabeprazole
sodium powder from each formula, previously
shaken to break any agglomerates formed, was
introduced in to 10 ml measuring cylinder. After that
Estimation of Rabeprazole sodium
the initial volume was noted and the cylinder was
Two different solutions of Rabeprazole sodium were
allowed to fall under its own weight on to a hard
prepared in 0.1 N HCl and 6.8 pH phosphate buffer
surface from the height of 2.5cm at second intervals.
respectively. The UV spectras were taken using
Tapping was continued until no further change in
spectrophotometer. The UV maxima of Rabeprazole
volume was noted. Bulk density and Tapped density
sodium in 0.1 N HCl and 6.8 pH phosphate buffer
were calculated using the following equations.
were found to be 260 nm and 284 nm respectively.
Bulk density = weight of the powder blend/untapped
Formulation development of core pellets of
Tapped density = weight of the blend/Tapped volume
Rabeprazole sodium
The drug suspension was prepared by mixing
3. Compressibility Index
crosspovidone and Hydroxypropylmethyl cellulose in
The compressibility Index of the powder blend was
purified water. The suspension was then placed into
determined by Carr’s compressibility index. The
the spray gun system of Glatt fluid bed processor
machine and sprayed onto the sugar core pellets
while the Glatt machine was set in running condition.
Carr’s Index (%) = {(TD – BD) x 100} / TD
This would allow the drug to be evenly coated onto
the core pellets to form drug – coated spherical
4. Hausner’s ratio
pellets. The drug – coated pellets were dried under
Hausner’s ratio is a number that is correlated to the
flowability of a powder or granular material. The
ratio of tapped density to bulk density of the powders is called the Hausner’s ratio. It is calculated by the
Table 2: Formulation of different batches of Rabeprazole sodium core pellets Ingredients Formulations (quantities in gms) Hausner’s ratio (H) = TD / BD
Where TD = tapped density, BD = bulk density.
Drug excipients compatibility study
Drug excipients compatibility studies were carried
out by mixing the drug with various excipients in
different proportions. Studies were carried out in
flint vials at Accelerated conditions, 40±2oC
/75%RH±5% RH. The studies were conducted for 4
Table 3: composition of Subcoating solution
weeks and compared with control at 2 - 8 oC.
Material Quantity (%)
Physical observations of the blend were recorded at
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Preparation of Coating solution of Color coat
atomizing air pressure (1 to 3 bars), % fluidization
(10 to 30%) and percent solids content (7%) were
To prevent interaction between Rabeprazole sodium
adjusted and optimized. After finishing of the
and Colorcoat EC4S, seal coating of core pellets of
coating pellets were dried at 40o C and at 10%
Rabeprazole sodium was done by Colorcoat FC4S
fluidization. The coated pellets were removed and
until weight gain 8-10%. Coating solution was
prepared by dissolving Colorcoat FC4S in mixture of
Iso Propyl Alcohol (IPA) and Mehtylene Dichloride
Evaluation of Parameters
(MDC) under constant stirring for 15-20 minutes by
Description: Examine visually and record the Table 4: Composition of enteric coating solution Identification: The Retention time of the major peak
in the chromatogram of the sample preparation corresponds to that of the standard preparation as
Material Quantity (%) Moisture content: Take about 35ml of Methanol in
titration flask of Karl Fischer titrator and titrate with
Preparation of Coating solution of enteric coating
Karl Fischer reagent to end point. Grind the pellets
solution
to fine powder in a dry mortar, weigh accurately
Required quantities of solvents were weight in the
about 0.5mg of the sample, transfer quickly to the
beaker or other suitable vessel. Propeller stirrer was
titration flask, dissolve by stirring and titrate with
used for preparation of coating solution. Propeller
was kept in the center and as close to the bottom of
the vessel as possible, stir the mixture of solvents to
Bulk density:
form a vortex without entrapment of air in to the
the sample into a 100 ml measuring cylinder, tap the
liquid. After that required quantity of Eudragit L100-
measuring cylinder 10 to 15 times and record the
55 (for 30% weight gain) was added in the water and
volume occupied by the sample. Calculate the bulk
kept continuous stirring for 15-20 minutes.
Coating of core pellets Bulk density = Weight of the sample (g)
A protective coating solution was prepared by mixing
Volume occupied by sample (ml)
Opadry clear slowly in the solvent mixture of IPA
and MDC (60:40). This coating was then placed into
Gastric Resistance
the spray gun of the Glatt machine and sprayed onto
Chromatographic conditions Buffer: Dissolve 2.72 g of Potassium dihydrogen
the drug – coated pellets while the Glatt machine was
ortho phosphate and 0.525 g of Dipotassium
set in running condition. After the coating was
hydrogen ortho phosphate in 1000 ml of water
completed, the protective coating-covered pellets were again dried under warm air within the Glatt
Mobile phase: Prepare a mixture of Buffer and
Acetonitrile in the ratio of 60:40, and adjust pH to 7.4
Finally, an enteric coating agent was prepared by
with Potassium hydroxide solution, filter and degas.
mixing Eudragit L100-55 in a mixture of Isopropyl alcohol and Methylen dichloride. This coating agent
Preparation of 0.1 M NaOH: Dissolve 4 g of
was placed into the spray gun of the Glatt machine
and sprayed onto the protective coating-covered pellets to form the pharmaceutical pellets before final
Standard Preparation: Weigh about 80.0 mg
drying of the granules to complete the process of
Rabeprazole sodium working standard in to a 100 ml
making the enteric coating-covered pellets.
volumetric flask dissolve and dilute to volume with
Coating of pellets was done using Glatt fluid bed
0.1 M NaOH and mix. Transfer 2.0 ml of this
processor machine. First fixed quantity (1Kg) pellets
solution in to a 50 ml volumetric flask and dilute to
were put in the product chamber which was
readjusted at 50oC temperature for 5 – 10 minutes. Various parameters like spraying rate (8 to 25
gm/min), inlet air temperature (20 to 50oC),
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Sample Preparation: Weigh and transfer the pellets
apparatus and run for 2 hrs at 100 rpm. After 2 hrs
equivalent to 20 mg of Rabeprazole sodium
lift the paddles completely and drain out the acid
individually in each of the 6 dissolution jars,
carefully without loss of pellets. Then add 900 ml of
containing 900 ml of 0.1 M Hydrochloric acid which
pH 8.0 Phosphate buffer the temperature of which
has been equilibrated to the temperature of 37±0.50C.
has been equilibrated to 37±0.50C and run the
Immediately start the apparatus and run for 2 hours.
apparatus. After specified interval withdraw sample
After 2 hours lift the paddles. Drain the medium
about 10 ml from a zone midway between the surface
completely with out losing any pellet. Carefully
of the medium and top of the rotating blade and not
transfer the pellets in to a 50 ml volumetric flask
less than 1 cm from the vessel wall and filter through
individually with the aid of a funnel. Add about 25
0.45 micron membrane filter. Immediately transfer 5
ml of 0.1 M Sodium hydroxide and sonicate for 15
ml of filtrate into a 10 ml of volumetric flask already
minutes and shake for 15 minutes. Dilute to volume
containing 2 ml of 0.2 M sodium hydroxide solution.
with 0.1 M Sodium hydroxide and mix. Centrifuge a
Mix well immediately and dilute to volume with
portion of the preparation at about 3000 RPM for 15
minutes. Transfer 2.0 ml of the clear supernatant
liquid in to a 25 ml volumetric flask and dilute to
Procedure: Inject separately Standard and test
samples into Liquid chromatograph port and record
Procedure:
Preparation and the Sample Preparation into the
liquid chromatograph and record the area due to
Standard Preparation: Weigh accurately about
80.0 mg of Rabeprazole sodium working standard in
to a 100 ml volumetric flask. Dissolve and dilute to
Dissolution in buffer
volume with 0.1 N NaOH and mix. Transfer 2.0 ml
Dissolution Parameters
of this solution in to a 50 ml volumetric flask and
Medium : Initially run in 900ml of 0.1 N
dilute to volume with mobile phase and mix.
Sample Preparation: Grind about 10g of pellets to
fine powder in a dry mortar and weigh accurately the
Volume : 1000ml
quantity of powder equivalent to 20 mg of
Apparatus : USP-II (paddle)
Rabeprazole sodium in to a 50 ml volumetric flask.
Speed : 100 rpm
Add 25 ml of 0.1N NaOH and dissolve the content by
Temp : 37±0.50C
sonicating for 15 min followed by shaking for 10
Sampling points : 2hr in acid and 10, 20 and
min, dilute to volume with 0.1N NaOH and mix.
Centrifuge a portion of the sample at 3000 RPM for
Standard Preparation: Weigh accurately 80.0 mg
10 min. Transfer 2 ml of the clear supernatant in to a
of Rabeprazole Sodium working standard into a 100
25 ml volumetric flask and dilute to volume with
ml volumetric flask, dissolve in 10 ml of 0.1 M
NaOH and dilute to volume with 0.1M NaOH.
Pipette out 2.0 ml above stock solution into a 100 ml
RESULTS AND DISCUSSION
of volumetric flask, which contains 20 ml of 0.2 M
Preformulation studies
sodium hydroxide mix immediately, and dilute to 100
From the results of Micromeritic studies of the
Rabeprazole sodium has poor flow property and
Sample preparation: Transfer 900 ml of 0.1 N Hcl
compressibility property. From the physical
into each of six dissolution jars the temperature of
which has been equilibrated to 37±0.50C. Transfer
interaction was notified. So it was concluded that
the weighed pellets equivalent to 20 mg of
drug and other excipients were compatible with each
Rabeprazole Sodium in to each of six jars. Start the
Table 5: Micromeritic properties of API Angle of repose (o) Compressibility Index Hausner’s ratio www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012 ______________________________________________________________________________

Table 6: Drug Excipient compatibility study (Physical observation) Batch no. Drug-Excipients combinationD:E RatioFinal description observation 1M/ (400C / 75%RH Evaluation parameters of the optimized batch of
storage conditions were not found any significant
Rabeprazole sodium
changes in final formulation dissolution profile with
From the results of comparative study of dissolution
profile of final batch with market preparations. It
was concluded that final formulation was shown
EVALUATION OF MARKET SAMPLE
The assay of the Market sample was found to be
Accelerated stability study of the optimized batch
From the results of the accelerated stability of the
final formulation for 3 months, it was concluded that
ACID RESISTANCE
Amount of the drug resisted after 2 hr in acid was
DISSOLUTION Table 7: Dissolution comparison of F2 sample (capsule) with Market sample in pH 8.0 buffer Time (min) Market sample InVitro dissolution profileTime (min) www.ijapbc.com IJAPBC – Vol. 1(1), Jan- Mar, 2012 ______________________________________________________________________________

From the above results, we found that F1, F2 , F3 and
dissolution profile. So finally F2 was found to be
F4 batches passed in assay and acid resistance tests.
best formula for formulation of Rabeprazole sodium
In sub coating process, the pellets were coated to 8%
and enteric build up was given upto 30 percentages.
Even though acid resistance test passed at 28 %
STABILITY SELECTED
enteric build up for safer side we coated up to 30% of
FORMULATION (F2)
Stability studies were conducted at 40ºC / 75% RH
Based on results, F2 formulation was found to be
for about 3 months in stability chamber (thermo lab).
satisfactory as it matched with the market sample
Samples were collected at 1, 2 and 3 months.
Table 11: Stability dataTemperature 40ºC / 75% RH Dissolution profile of selected stability sampleT ime (mins)

Selected formulation F2 was kept for stability studies and observed that assay, acid resistance and drug release at the end of 1, 2 and 3 months. There was no significant change in in-vitro release profile. It shows that formulation F2 was stable. SUMMARY AND CONCLUSIONThe aim of the present study was to formulate and evaluate delayed release pellets of Rabeprazole sodium by enteric coating. It is an acid labile drug so it is degraded at acidic pH of stomach so an attempt was made to stabilize the drug with super disintegrant with different particle size and alkaline agent Sodium carbonate. Finally enteric coating was given to bypass the stomach. The enteric coating was carried out by using enteric polymer Methacrylic acid copolymer Eudragit L 30D-55. The study includes preformulation of drug and excipients, formulation, evaluation and stability studies of delayed release pellets.
The core pellets were prepared using suspension layering
technique in fluid bed process. Sub coating was given to core pellets to avoid direct contact of drug with enteric coating materials. Sub coating was given with Opadry clear which contains HPMC, diethyl phthalate which was dispersed in isopropyl alcohol & methylene-di-chloride acting as a solvents system. An average weight build up of 8%w/w was given to core pellets.
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